Background: Mucinous cystic neoplasm (MCN) is one of the precursors of invasive pancreatic carcinoma. The molecular alterations that take place during the progression of MCNs, however, have not been fully elucidated, with most of the literature focusing on the non-invasive examples.Design: Immunolabeling of mucin core proteins (MUC1, MUC2, MUC 5AC, MUC6, CDX2), p53 and DPC4 were examined in 40 MCNs, consisting of 9 low-grade (LG), 8 high-grade (HG) and 23 with an associated invasive carcinoma. Mutational analysis for BRAF and KRAS was performed in 15 (4LG, 6HG, 5 invasive).Results: Gastric lineage markers (MUC5AC and MUC6) were detected only in the cystic/LG areas and were virtually absent in papillary/HG components or invasion. Intestinal differentiation markers were not detected in carcinogenetic spectrum of MCNs, with the exception of metaplastic goblet cells highlighted by MUC2, and rare areas of cystic/LG components of the tumors showing weak CDX2 labeling. MUC1 (pancreatobiliary lineage marker) was expressed only in advanced lesions [50% (4/8) HG and 92% (20/23) of invasive]. Similarly, p53, if present, was detected only in advanced lesions; 25% (2/8) of HG and 39% (9/23) of invasive carcinoma. DPC4 stain was retained in most MCN cases except for 4 (17%) of invasive carcinoma. Immunophenotypic changes are summarized in Table 1. No BRAF mutations were identified, but KRAS was mutated in advanced lesions: 5/6 HG and 5/5 invasive (Table 2).

Table 1. Immunophenotypic changes of MCN

MUC1

MUC2

CDX2

MUC5AC

MUC6

P53

DPC4

Low-grade (n=9)

0

0

0

4/9 (44%)

4/9 (44%)

0

8/9 (89%)

High-grade/CIS (n=8)

4/8 (50%)

1/8 (13%)

1/8 (13%)

0

2/8 (25%)

2/8 (25%)

7/8 (88%)

Invasive ca (n=23)

20/23 (92%)

0

0

2/23 (9%)

1/23 (4%)

9/23 (39%)

19/23 (83%)

Table 2. Mutational study of BRAF and KRAS in MCN

Low-grade (n=4)

High-grade (n=6)

Invasive ca. (n=5)

BRAF

0

0

0

KRAS

0

5/6

5/5

Conclusions: At immunohistochemical and molecular levels, MCN pathway of carcinogenesis in the pancreas is of the pancreatobiliary lineage, showing similarities to the PanIN pathway and is dissimilar from the IPMN of intestinal or oncocytic types. Thus it is not surprising that the invasive carcinomas in MCNs are almost exclusively of tubular type (not colloid) and have aggressive behavior, as shown recently. BRAF mutation is not involved in MCN carcinogenesis.Category: Pancreas